Journal of Clinical Immunology

, Volume 28, Issue 5, pp 486–494 | Cite as

Elevated Serum Anti-Saccharomyces cerevisiae, Anti-I2 and Anti-OmpW Antibody Levels in Patients with Suspicion of Celiac Disease

  • Sara Ashorn
  • Hanna Raukola
  • Tuuli Välineva
  • Merja Ashorn
  • Bo Wei
  • Jonathan Braun
  • Immo Rantala
  • Katri Kaukinen
  • Tiina Luukkaala
  • Pekka Collin
  • Markku Mäki
  • Sari Iltanen
Article

Abstract

Objectives

Expression of anti-Saccharomyces cerevisiae antibodies (ASCA) identifies patients and individuals at risk for Crohn’s disease and has also been reported in 40–60% of celiac disease (CD) cases, suggesting a role of host response to enteric microbiota in the development of inflammatory lesions. In this prospective study in patients with suspicion of CD, we evaluate the frequency and association of ASCA to serological responses for other host microbial targets formally associated with Crohn’s disease, including the Pseudomonas fluorescens associated sequence I2 and a Bacteroides caccae TonB-linked outer membrane protein, OmpW.

Methods

Small bowel mucosal biopsies were taken from 242 patients with suspicion of CD, their sera were tested for antibodies to tissue transglutaminase (tTG), ASCA, I2, and OmpW. Eighty adult healthy blood donors were used as controls.

Results

The diagnosis of CD was confirmed on biopsy in 134 cases. The occurrence of ASCA and I2 positivity was significantly higher in adult CD patients than in patients with non-CD disease. Anti-I2 levels in the sera were significantly higher in adult CD patients than in non-CD disease or the controls and anti-OmpW levels in CD and non-CD patients when compared to controls. Positive seroreactivity to OmpW seemed to increase with age. Of the CD patients, 90% were seropositive for at least one microbial antigen tested.

Conclusions

This study demonstrates a mosaic of disease-related serological responses to microbial antigens in patients with CD. Immune responses to commensal enteric bacteria may play a role in the small intestine mucosal damage in CD.

Keywords

Tissue transglutaminase I2 OmpW ASCA serology celiac disease 

References

  1. 1.
    Walker-Smith JA, Guandalini S, Schmitz J, et al. Revised criteria for diagnosis of coeliac disease. Arch Dis Child. 1990;65:909–11.Google Scholar
  2. 2.
    Mäki M, Holm K, Koskimies S, Hällström O, Visakorpi JK. Normal small bowel biopsy followed by coeliac disease. Arch Dis Child. 1990;65:1137–41.PubMedGoogle Scholar
  3. 3.
    Marsh MN. Gluten, major histocompatibility complex, and the small intestine. A molecular and immunobiologic approach to the spectrum of gluten sensitivity (“celiac sprue”). Gastroenterology. 1992;102:330–54.PubMedGoogle Scholar
  4. 4.
    Dietrich W, Ehnis T, Bauer M, Donner P, Volta U, Riecken EO, Schuppan D. Identification of tissue transglutaminase as the autoantigen of celiac disease. Nat Med. 1997;3:797–801.CrossRefGoogle Scholar
  5. 5.
    Troncone R, Maurano F, Rossi M, Micillo M, Greco L, Auricchio R, Salerno G, Salvatore F, Sacchetti L. IgA antibodies to tissue transglutaminase: an effective diagnostic test for celiac disease. J. Pediatr. 1999;134:166–71.PubMedCrossRefGoogle Scholar
  6. 6.
    Salmi TT, Collin P, Maki M, Laurila K, Partanen J, Huhtala H, Király R, Lorand L, Reunala T, Mäki M, Kaukinen K. Immunoglobulin a autoantibodies against transglutaminase 2 in the small intestinal mucosa predict forthcoming celiac disease. Aliment Pharmacol Ther. 2006 1;24:541–52.PubMedCrossRefGoogle Scholar
  7. 7.
    Sjöberg K, Eriksson S, Tenngart B, Bodil Roth E, Leffler H, Stenberg P. Factor XIII and tissue transglutaminase antibodies in coeliac and inflammatory bowel disease. Autoimmunity. 2002;35:357.CrossRefGoogle Scholar
  8. 8.
    Main J, McKenzie H, Yeaman GR. Antibody to Saccharomyces cerevisiae (baker’s yeast) in patients with Crohn’s disease. BMJ. 1988;297:1105–6.PubMedCrossRefGoogle Scholar
  9. 9.
    McKenzie H, Main J, Pennington CR, Kerr MA, Robson D, Pennington CR, Parratt D. Antibody to selected strains of Saccharomyces cerevisiae (baker’s and brewer’s yeast) and Candida albicans in Crohn’s disease. Gut. 1990;31:536–8.PubMedCrossRefGoogle Scholar
  10. 10.
    Vasiliauskas EA, Kam LY, Karp LC, Gaiennie J, Yang H, Targan SR. Marker antibody expression stratifies Crohn’s disease into immunologically homogeneous subgroups with distinct clinical characteristics. Gut. 2000;47:487–96.PubMedCrossRefGoogle Scholar
  11. 11.
    Dubinsky MC, Ofman JJ, Urman M, Targan SR, Seidman EG. Clinical utility of serodiagnostic testing in suspected pediatric inflammatory bowel disease. Am J Gastroenterol. 2001;96:758–65.PubMedCrossRefGoogle Scholar
  12. 12.
    Arnott ID, Landers CJ, Nimmo EJ, Drummond HE, Smith BK, Targan SR, Satsangi J. Sero-reactivity to microbial components in Crohn’s disease is associated with disease severity and progression, but not NOD2/CARD15 genotype. Am J Gastroenterol. 2004;99:2376–84.PubMedCrossRefGoogle Scholar
  13. 13.
    Iltanen S, Tervo L, Halttunen T, Wei B, Braun J, Rantala I, Honkanen T, Kronenberg M, Cheroutre H, Turovskaya O, Autio V, Ashorn M. Elevated serum anti-I2 and anti-OmpW antibody levels in children with IBD. Inflamm Bowel Dis. 2006;12:389–94.PubMedCrossRefGoogle Scholar
  14. 14.
    Halfvarson J, Standaert-Vitse A, Järnerot G, Sendid B, Jouault T, Bodin L, Duhamel A, Colombel JF, Tysk C, Poulain D. Anti-Saccharomyces cerevisiae antibodies in twins with inflammatory bowel disease. Gut. 2005;54:1237–43.PubMedCrossRefGoogle Scholar
  15. 15.
    Damoiseaux J, Bouten B, Linders A, Austen J, Roozendaal C, Russel MG, Forget PP, Tervaert JW. Diagnostic value of anti-Saccharomyces cerevisiae and antineutrophil cytoplasmic antibodies for inflammatory bowel disease: high prevalence in patients with celiac disease. J Clin Immunol. 2002;22(5):281–8. Sep.PubMedCrossRefGoogle Scholar
  16. 16.
    Granito A, Zauli D, Muratori P, Muratori L, Grassi A, Bortolotti R, Petrolini N, Veronesi L, Gionchetti P, Bianchi FB, Volta U. Anti-Saccharomyces cerevisiae and perinuclear antineutrophil cytoplasmic antibodies in coeliac disease before and after gluten-free diet. Aliment Pharmacol Ther. 2005;21:881–7.PubMedCrossRefGoogle Scholar
  17. 17.
    Ahmad T, Marshall SE, Jewell D. Genetics of inflammatory bowel disease: the role of the HLA complex. World J Gastroenterol. 2006;12:3628–35.PubMedGoogle Scholar
  18. 18.
    Rioux JD, Daly MJ, Silverberg MS, Steinhart AH, McLeod RS, Griffiths AM, Green T, Brettin TS, Stone V, Bull SB, Bitton A, Williams CN, Greenberg GR, Cohen Z, Lander ES, Hudson TJ, Siminovitch KA. Genetic variation in the 5q31 cytokine gene cluster confers susceptibility to Crohn disease. Nat Genet. 2001;29:223–8. Oct.PubMedCrossRefGoogle Scholar
  19. 19.
    Amundsen SS, Adamovic S, Hellqvist A, Nilsson S, Gudjónsdóttir AH, Ascher H, Ek J, Larsson K, Wahlström J, Lie BA, Sollid LM, Naluai AT: A comprehensive screen for SNP associations on chromosome region 5q31–33 in Swedish/Norwegian celiac disease families. Eur J Hum Genet. 2007;15:980–7.Google Scholar
  20. 20.
    Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature. 2007;447:661–78.CrossRefGoogle Scholar
  21. 21.
    Sartor RB. Induction of mucosal immune responses by bacteria and bacterial components. Curr Opin Gastroenterol. 2001;17:555–61.PubMedCrossRefGoogle Scholar
  22. 22.
    Landers CJ, Cohavy O, Misra R, Yang H, Lin YC, Braun J, Targan SR. Selected loss of tolerance evidenced by Crohn’s disease associated immune responses to auto- and microbial antigens. Gastroenterology. 2002;123:689–99.PubMedCrossRefGoogle Scholar
  23. 23.
    Sutton CL, Kim J, Yamane A, Dalwadi H, Wei B, Landers C, Targan SR, Braun J. Identification of a novel bacterial sequence associated with Crohn’s disease. Gastroenterology. 2000;119:23–31.PubMedCrossRefGoogle Scholar
  24. 24.
    Wei B, Dalwadi H, Gordon LK, Landers C, Bruckner D, Targan SR, Braun J. Molecular cloning of a Bacteroides caccae TonB-linked outer membrane protein identified by an inflammatory bowel disease marker antibody. Infect Immun. 2001;69:6044–54.PubMedCrossRefGoogle Scholar
  25. 25.
    Polymeros D, Bogdanos DP, Day R, Arioli D, Vergani D, Forbes A. Does cross-reactivity between mycobacterium avium paratuberculosis and human intestinal antigens characterize Crohn’s disease? Gastroenterology. 2006;131:85–96.PubMedCrossRefGoogle Scholar
  26. 26.
    Papp M, Altorjay I, Norman GL, Shums Z, Palatka K, Vitalis Z, Foldi I, Lakos G, Tumpek J, Udvardy ML, Harsfalvi J, Fischer S, Lakatos L, Kovacs A, Bene L, Molnar T, Tulassay Z, Miheller Veres G, Papp J, Lakatos PL, Hungarian IBD Study Group. Seroreactivity to microbial components in Crohn’s disease is associated with ileal involvement, noninflammatory disease behavior and NOD2/CARD15 genotype, but not with risk for surgery in a Hungarian cohort of IBD patients. Inflamm Bowel Dis. 2007;13:984–92.PubMedCrossRefGoogle Scholar
  27. 27.
    Clancy R, Ren Z, Turton J, Pang G, Wettstein A. Molecular evidence for Mycobacterium avium subspecies paratuberculosis (MAP) in Crohn’s disease correlates with enhanced TNF-alpha secretion. Dig Liver Dis. 2007;39:445–51.PubMedCrossRefGoogle Scholar
  28. 28.
    Garcia-Lafuente A, Antolin M, Guarner F, Crespo E, Salas A, Forcada P, Laguarda M, Gavaldá J, Baena JA, Vilaseca J, Malagelada JR. Incrimination of anaerobic bacteria in the induction of experimental colitis. Am J Physiol. 1997;272:G10–G15.PubMedGoogle Scholar
  29. 29.
    Ley RE, Peterson DA, Gordon JI. Ecological and evolutionary forces shaping microbial diversity in the human intestine. Cell. 2006;124:837–48.PubMedCrossRefGoogle Scholar
  30. 30.
    Sulkanen S, Collin P, Laurila K, Mäki M. IgA and IgG-class antihuman umbilical cord antibody tests in adult coeliac disease. Scand J Gastroenterol. 1998;33:251–4.PubMedCrossRefGoogle Scholar
  31. 31.
    Kuitunen P, Kosnai I, Savilahti E. Morphometric study of the jejunal mucosa in various childhood enteropathies with special reference to intraepithelial lymphocytes. J Pediatr Gastroenterol Nutr. 1982;1:525–31.PubMedCrossRefGoogle Scholar
  32. 32.
    Korponay-Szabo IR, Laurila K, Szondy Z, Halttunen T, Szalai Z, Dahlbom I, Rantala I, Kovács JB, Fésüs L, Mäki M. Missing endomysial and reticulin binding of coeliac antibodies in transglutaminase 2 knockout tissues. Gut. 2003;52:199–204.PubMedCrossRefGoogle Scholar
  33. 33.
    Reese GE, Constantinides VA, Simillis C, Darzi AW, Orchard TR, Fazio VW, Tekkis PP. Diagnostic precision of anti-Saccharomyces cerevisiae antibodies and perinuclear antineutrophil cytoplasmic antibodies in inflammatory bowel disease. Am J Gastroenterol. 2006;101:2410–22.PubMedCrossRefGoogle Scholar
  34. 34.
    Giaffer MH, Clark A, Holdsworth CD. Antibodies to Saccharomyces cerevisiae in patients with Crohn’s disease and their possible pathogenic importance. Gut. 1992;33:1071–5.PubMedCrossRefGoogle Scholar
  35. 35.
    Mallant-Hent RCh, Mary B, von Blomberg E, Yüksel Z, Wahab PJ, Gundy C, Meyer GA, Mulder CJ. Disappearance of anti-Saccharomyces cerevisiae antibodies in coeliac disease during a gluten-free diet. Eur J Gastroenterol Hepatol. 2006;18:75–8.PubMedCrossRefGoogle Scholar
  36. 36.
    Desplat-Jego S, Johanet C, Escande A, Goetz J, Fabien N, Olsson N, Ballot E, Sarles J, Baudon JJ, Grimaud JC, Veyrac M, Chamouard P, Humbel RL. Update on Anti-Saccharomyces cerevisiae antibodies, anti-nuclear associated anti-neutrophil antibodies and antibodies to exocrine pancreas detected by indirect immunofluorescence as biomarkers in chronic inflammatory bowel diseases, Results of a multicenter study. World J Gastroenterol. 2007;13(16):2312–8. Apr 28.PubMedGoogle Scholar
  37. 37.
    Toumi D, Mankai A, Belhadj R, Ghedira-Besbes L, Jeddi M, Ghedira I. Anti-Saccharomyces cerevisiae antibodies in coeliac disease. Scand J Gastroenterol. 2007;42(7):821–6. Jul..PubMedCrossRefGoogle Scholar
  38. 38.
    Peeters M, Geypens B, Claus D, Nevens H, Ghoos Y, Verbeke G, Baert F, Vermeire S, Vlietinck R, Rutgeerts P. Clustering of increased small intestinal permeability in families in Crohn’s disease. Gasteroenterolog. 1997;113:802–7.CrossRefGoogle Scholar
  39. 39.
    Clemente MG, De Virgiliis S, Kang JS, Macatagney R, Musu MP, Di Pierro MR, Drago S, Congia M, Fasano A. Early effects of gliadin on enterocyte intracellular signalling involved in intestinal barrier function. Gut. 2003;52:218–23.PubMedCrossRefGoogle Scholar
  40. 40.
    Drago S, El Asmar R, Di Pierro M, Grazia Clemente M, Tripathi A, Sapone A, Thakar M, Iacono G, Carroccio A, D’Agate C, Not T, Zampini L, Catassi C, Fasano A. Gliadin, zonulin and gut permeability: effects on celiac and non-celiac intestinal mucosa and intestinal cell lines. Scand J Gastroenterol. 2006;41:408–19.PubMedCrossRefGoogle Scholar
  41. 41.
    Sendid B, Quinton JF, Charrier G, Goulet O, Cortot A, Grandbastien B, Poulain D, Colombel JF. Anti-Saccharomyces cerevisiae mannan antibodies in familial Crohn’s disease. Am J Gastroenterol. 1998;93:1306–10.PubMedCrossRefGoogle Scholar
  42. 42.
    Sutton CL, Yang H, Li Z, Rotter JI, Targan SR, Braun J. Familial expression of anti-Saccharomyces cerevisiae mannan antibodies in affected and unaffected relative of patients with Crohn’s disease. Gut. 2000;46:58–63.PubMedCrossRefGoogle Scholar
  43. 43.
    Vermeire S, Peeters M, Vlietinck R, Joossens S, Den Hond E, Bulteel V, Bossuyt X, Geypens B, Rutgeerts P. Anti-Saccharomyces cerevisiae antibodies (ASCA), phenotypes of IBD, and intestinal permeability: a study in IBD families. Inflamm Bowel Dis. 2001;7:8–15.PubMedCrossRefGoogle Scholar
  44. 44.
    Kaila B, Orr K, Bernstein CN. The anti-Saccharomyces cerevisiae antibody assay in a province wide practice: accurate in identifying cases of Crohn’s disease and predicting inflammatory disease. Can J Gastroenterol. 2005;19:717–21.PubMedGoogle Scholar
  45. 45.
    van Elburg RM, Uil JJ, Mulder CJ, Heymans H. Intestinal permeability in patients with coeliac disease and relatives of patients with coeliac disease. Gut. 1993;34:354–7.PubMedCrossRefGoogle Scholar
  46. 46.
    Sander GR, Cummins AG, Henshall T, Powell BC. Rapid disruption of intestinal barrier function by gliadin involves altered expression of apical junctional proteins. FEBS Lett. 2005;579:4851–5.PubMedCrossRefGoogle Scholar
  47. 47.
    Ciccocioppo R, Finamore A Ara C, Di Sabatino A, Mengheri E, Corazza GR. Altered expression, localization, and phosphorylation of epithelial junctional proteins in celiac disease. Am J Clin Pathol 2006;125:502–11.PubMedGoogle Scholar
  48. 48.
    Granito A, Muratori L, Muratori P, Guidi M, Lenzi M, Bianchi FB, Volta U. Anti-Saccaharomyces cerevisiae antibodies (ASCA) in coeliac disease. Gut. 2006;55:296.PubMedGoogle Scholar
  49. 49.
    Dubinsky MC, Lin YC, Dutridge D, Picornell Y, Landers CJ, Farrior S, Wrobel I, Quiros A, Vasiliauskas EA, Grill B, Israel D, Bahar R, Christie D, Wahbeh G, Silber G, Dallazadeh S, Shah P, Thomas D, Kelts D, Hershberg RM, Elson CO, Targan SR, Taylor KD, Rotter JI, Yang H, Western Regional Pediatric IBD Research Alliance. : Serum immune responses predict rapid disease progression among children with Crohn’s disease: immune responses predict disease progression. Am J Gastroenterol. 2006;101:360–7.PubMedCrossRefGoogle Scholar
  50. 50.
    Mow WS, Vasiliauskas EA, Lin YC, Fleshner PR, Papadakis KA, Taylor KD, Landers CJ, Abreu-Martin MT, Rotter JI, Yang H, Targan SR. Association of antibody responses to microbial antigens and complications of small bowel Crohn’s disease. Gastroenterology. 2004;126:414–24.PubMedCrossRefGoogle Scholar
  51. 51.
    Ferrante M, Henckaerts L, Joossens M, Pierik M, Joossens S, Dotan N, Norman GL, Altstock RT, Van Steen K, Rutgeerts P, Van Assche G, Vermeire S. New serological markers in inflammatory bowel disease are associated with complicated disease behaviour. Gut. 2007;56:1394–403.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Sara Ashorn
    • 1
  • Hanna Raukola
    • 3
  • Tuuli Välineva
    • 6
  • Merja Ashorn
    • 1
    • 2
  • Bo Wei
    • 8
  • Jonathan Braun
    • 8
  • Immo Rantala
    • 4
  • Katri Kaukinen
    • 1
    • 5
  • Tiina Luukkaala
    • 7
  • Pekka Collin
    • 5
  • Markku Mäki
    • 1
    • 2
  • Sari Iltanen
    • 1
    • 9
  1. 1.Paediatric Research Centre and Medical SchoolUniversity of Tampere and Tampere University HospitalTampereFinland
  2. 2.Department of PaediatricsTampere University HospitalTampereFinland
  3. 3.Department of MicrobiologyTampere University HospitalTampereFinland
  4. 4.Department of PathologyTampere University HospitalTampereFinland
  5. 5.Department of Gastroenterology and Alimentary Tract SurgeryTampere University HospitalTampereFinland
  6. 6.Institute of Medical TechnologyUniversity of TampereTampereFinland
  7. 7.Research Unit, Tampere University Hospital and Tampere School of Public HealthUniversity of TampereTampereFinland
  8. 8.Department of Pathology and Laboratory MedicineUniversity of CaliforniaLos AngelesUSA
  9. 9.Paediatric Research CentreUniversity of TampereTampereFinland

Personalised recommendations